(Taken from the application): Neonatal lupus is currently considered a model of passively acquired autoimmunity whereby immune abnormalities in the mother (who may have systemic lupus erythematosus, Sjogrens syndrome, or be entirely asymptomatic) lead to the production of antibodies to the SSA/Ro-SSB/La ribonucleoproteins which cross the placenta and presumably injure the developing fetus. The most serious manifestation is cardiac injury which includes varying degrees of atrioventricular (AV) block, most often third degree, and myocarditis. The mortality approaches 20% and the majority of children require lifelong pacing. This application focuses both on the clinical approach to diagnosed congenital heart block (CHB) [interventional study] and the search for an early echocardiographic marker of injury [observational study].
In Specific Aim 1, a randomized double-blind placebo-controlled trial will examine the effect of daily oral dexamethasone (4 mg) on the outcome of CHB. The rationale rests on the hypothesis that CHB is the consequence of an inflammatory process mediated by maternal anti-Ro/La antibodies. Mothers, irrespective of disease activity but requiring less than 10 mg prednisone/day, identified before 30 weeks of gestation to be carrying a fetus with CHB, will be randomized to receive dexamethasone or placebo (50 patients per arm) for a minimum of 6 weeks. Primary outcome measures include neonatal ventricular rate and ejection fraction at birth, and presence or absence of abnormal fluid collection as assessed on the final fetal echocardiogram before delivery. Secondary outcome measures include the degree of block at birth, gestational age, birth weight, and cardiothoracic ratio.
In Specific Aim 2, we will attempt to identify the earliest noninvasive echocardiographic marker of AV nodal dysfunction and/or myocardial injury. At present it is not known whether injury to the AV node progresses through stages with the final outcome being fibrosis of the node and irreversible third degree block. It has been proposed that global inflammation of the working myocardium and surrounding pericardium may precede or accompany AV nodal injury. One hundred pregnant women considered at high risk for having a child with CHB, as defined by presence of Ro/La antibodies documented prior to pregnancy (regardless of whether or not they have had a previous child with neonatal lupus), will be followed by weekly echocardiograms from 16 weeks of gestation, with special attention to prolongation of the mechanical PR interval and/or development of myocardial dysfunction. Mothers whose fetuses develop 1st, 2nd or 3rd degree block will then be randomized to receive either dexamethasone or placebo as part of Specific Aim 1. The importance of this second aim is twofold: first, it will identify whether the subclinical incidence of tissue injury exceeds overt injury manifest as advanced AV dissociation; and second, it will provide the best chance for reversibility of block given identification of early lesions.
Showing the most recent 10 out of 13 publications
